1. Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma.
- Author
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Lee SH, Do SI, Lee HJ, Kang HJ, Koo BS, and Lim YC
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics, Animals, Antineoplastic Agents pharmacology, Carcinoma, Squamous Cell genetics, Cell Line, Tumor, Cisplatin pharmacology, Female, Gene Expression drug effects, Gene Knockdown Techniques, Head and Neck Neoplasms genetics, Humans, Male, Mice, Mice, Inbred BALB C, Middle Aged, Multidrug Resistance-Associated Protein 2, Multidrug Resistance-Associated Proteins genetics, Neoplasm Proteins genetics, Prognosis, Receptor, Notch1 antagonists & inhibitors, Receptor, Notch1 genetics, Signal Transduction, Squamous Cell Carcinoma of Head and Neck, Wnt Signaling Pathway, Xenograft Model Antitumor Assays, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms pathology, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Receptor, Notch1 metabolism
- Abstract
Notch1 is associated with the initiation and progression of various solid tumors. However, the exact role of Notch1 expression in head and neck squamous cell carcinoma (HNSCC) remain unclear. We created cells ectopically expressing notch intracellular domain (NICD) from previously established HNSCC cells and examined self-renewal capacity and stem cell markers' expression compared with control cells. In addition, we knocked Notch1 down in primary spheres obtained from HNSCC tumor tissue and assessed the attenuation of stemness-associated traits in these cells in vitro and in vivo. Furthermore, we examined clinical relevance of Notch1 expression in HNSCC patients. Constitutive activation of NICD promoted the self-renewal capacity of HNSCC cells by activating sphere formation and increased the expression of stem cell markers such as Oct4, Sox2, and CD44. In contrast, Notch1 knockdown in primary HNSCC cancer stem cells (CSCs) attenuated CSC traits and augmented the chemosensitizing effects of cisplatin along with the decreased expression of almost all of ABC transporter genes. In addition, Notch1 knockdown in HNSCC CSCs inhibited tumor formation and increased survival of mice in a xenograft model. Also, Notch1 acted upstream of canonical Wnt signaling in HNSCC cells. Finally, elevated Notch1 expression is associated with poor prognosis in patients with HNSCC. In conclusion, Notch1 may be a critical regulator of stemness in HNSCC cells, and inactivation of this pathway could be a potential targeted approach for the treatment of HNSCC.
- Published
- 2016
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